Acylguanidines as bioisosteres of guanidines: NG-acylated imidazolylpropylguanidines, a new class of histamine H2 receptor agonists.
N1-Aryl(heteroaryl)alkyl-N2-[3-(1H-imidazol-4-yl)propyl]guanidines are potent histamine H2-receptor (H2R) agonists, but their applicability is compromised by the lack of oral bioavailability and CNS penetration. To improve pharmacokinetics, we introduced carbonyl instead of methylene adjacent to the guanidine moiety, decreasing the basicity of the novel H2R agonists by 4-5 orders of magnitude. Some acylguanidines with one phenyl ring were even more potent than their diaryl analogues. As demonstrated by HPLC-MS, the acylguanidines (bioisosteres of the alkylguanidines) were absorbed from the gut of mice and detected in brain. In GTPase assays using recombinant receptors, acylguanidines were more potent at the guinea pig than at the human H2R. At the hH1R and hH3R, the compounds were weak to moderate antagonists or partial agonists. Moreover, potent partial hH4R agonists were identified. Receptor subtype selectivity depends on the imidazolylpropylguanidine moiety (privileged structure), opening an avenue to distinct pharmacological tools including potent H4R agonists.
Ghorai
Prasanta
P
Departments of Pharmaceutical/Medicinal Chemistry, University of Regensburg, D-93053 Regensburg, Germany.
Kraus
Anja
A
Keller
Max
M
Götte
Carsten
C
Igel
Patrick
P
Schneider
Erich
E
Schnell
David
D
Bernhardt
Günther
G
Dove
Stefan
S
Zabel
Manfred
M
Elz
Sigurd
S
Seifert
Roland
R
Buschauer
Armin
A
D000215:Acylation; D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D017442:Histamine Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011970:Receptors, Histamine H2 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013997:Time Factors
D006146:Guanidines; D017442:Histamine Agonists; D007093:Imidazoles; D011970:Receptors, Histamine H2